PROJECT SUMMARY The first step of vision takes place in the retina where light is captured by the outer segment of photoreceptor cells. This light-sensing organelle is a modified primary cilium with a unique architechture (hundreds of tightly stacked disc membranes enclosed by a plasma membrane) that contains an elite set of signaling and structural proteins. Since proteins are synthesized in the cell soma they require discrete intracellular trafficking mechanisms to be delivered to the outer segment. These trafficking mechanisms are critical for development and general maintenance of photoreceptors, as the outer segment is a dynamic structure that must be continuously renewed. Understanding mechanisms governing subcellular distribution of proteins remains a central unsolved problem in cell biology. As a new investigator, I will use my expertise in biochemistry, cell biology, molecular genetics, and retinal neurobiology to explore the mechanisms involved in delivering signaling and structural proteins to their final destination. My research will focus on investigating the outer segment trafficking of disc and plasma membrane proteins, as well as elucidating how outer segment proteins are segregated between the two functional membrane subdomains ? discs and plasma membrane. My proposal has broad implications to understanding the pathobiological processes underlying cases of retinal degenerative diseases and ciliopathy disorders.